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Asbestos induces AP-1 activation in cell culture and transgenic mice.

Occupational exposure to asbestos is linked to increased incidence of lung cancer. To investigate the carcinogenic mechanism of asbestos, activation of activator protein (AP-1) by crocidolite asbestos was examined in both a stable AP-1-luciferase reporter plasmid-transfected JB6 p+ cell line and AP-1-luciferase reporter transgenic mice. In the cultured cells asbestos caused a dose-dependent induction of AP-1 activation. The elevated AP-1 activity persisted at least for 48 hours. Asbestos also induced AP-1 transactivation in transgenic mice. AP-1 activation was observed at 2 days after exposure of the mice to asbestos via intratracheal instillation. At 3 days post-exposure, the AP-1 was elevated 10-fold in the lung tissue and 22-fold in bronchial tissue as compared to their controls. This finding is consistent with previous reports showing that asbestos causes site specific bronchogenic carcinoma. The induction effect of asbestos-induced AP-1 activity appeared to be mediated through the activation of MAP kinase family members, including extracellular signal-regulated protein kinases, Erk1 and Erk2. Aspirin inhibited asbestos-induced AP-1 activity in JB6 cells. Pretreatment of the mice with aspirin also inhibited asbestos-induced AP-1 activation. The data suggest that further investigation of the involvement of AP-1 in asbestos-induced cell proliferation and carcinogenesis as well as the potential therapeutic/preventative actions of aspirin in asbestos-induced carcinogenesis is warranted.